Synthesis and Spectral Characterization of Impurities of a COX-2 Selective Drug, Celecoxib

Full text of DOI:10.1002/bkcs.11720

Communication
DOI: 10.1002/bkcs.11720
BULLETIN OF THE
Y. H. Lee et al.
KOREAN CHEMICAL SOCIETY
Synthesis and Spectral Characterization of Impurities of a COX-2
Selective Drug, Celecoxib
Young Hee Lee,†,‡,¶ Manjunatha Vishwanath,‡,¶ Srinu Lanka,‡ Eunhwa Lee,† Yongbin Park,†
‡
Sunhwan Lee,† Jaeuk Sim,‡ Seohoo Lee,‡ Kiho Lee,§ Mayavan Viji,‡, Heesoon Lee,
*
and Jae-Kyung Jung‡,
*
†Samjin Central Research Institute, Samjin Pharma Co., LTD, Cheongju 28158, South Korea
‡College of Pharmacy, Chungbuk National University, Cheongju 28160, South Korea.
*E-mail: cheviji@gmail.com; orgjkjung@chungbuk.ac.kr
§College of Pharmacy, Korea University, Sejong 30019, South Korea
Received March 13, 2019, Accepted March 25, 2019
Keywords: Celecoxib, Impurities, Pyrazole, Active pharmaceutical ingredient, COX inhibitor
Introduction
Whereas the impurity B 3, formed due to reaction of 1,3
diketone 6 with traces of the water present in the reaction
mixture, afforded hydrate 9, which underwent condensation
with hydrazine 7 resulting the impurity B 3 (Scheme 2).9
Rheumatoid arthritis is one of the omnipresent autoimmune
disorders which leads to bone damage, skeletal disorders,
and disability.1 Celecoxib (1) the brand name Celebrex, is a
selective cyclooxygenase (COX)-2 inhibitor (coxib) used for
treatment of osteoarthritis, rheumatoid arthritis approved by
the FDA.2 Coxibs were developed to provide anti-inflamma-
tory/analgesic activity similar to that of nonselective non-
steroidal anti-inflammatory drugs (NSAIDs), but without
gastrointestinal toxicity resulting from COX-1 inhibition.3
Impurities are the unwanted chemical entities that are
formed during the process of synthesizing active pharmaceu-
tical ingredients (APIs) or during formulation of the drug.
Even in trace amounts the existence of the impurities may
affect the efficacy and safety of the drug. As per guideline
on impurities by International Conference on Harmonization
(ICH), it is mandatory to identify and characterize all the
impurities which are present 0.10% or more.4 As a part of
our continuing research on synthesis of pharmaceutically
important molecules, we aimed at synthesis of process impu-
rities of celecoxib.5 During the HPLC analysis of crude
celecoxib, two main impurities have been detected in the
range of 0.01-0.15%, which originated from the manufactur-
ing process of API. Initial analysis of HPLC and previous
reports suggested that the impurities are the regioisomers of
the celecoxib. Few reports are present in literature; however,
these methods involve multistep synthesis with low yields
and HPLC methods to identify these impurities are scarce.6
The synthetic strategy which is widely used to synthesize
the diarylpyrazole ring of celecoxib as follows, the conden-
sation reaction between hydrazine 7 with 1,3-dicarbonyl
compound 6 produce 1 (Scheme 1). One of the demerits of
this route was the formation of regioisomeric impurities.7
Impurity A 2, regioisomer is believed to originate from a
starting material 1,3 dicarbonyl compound 8 (Scheme 2).8
Results and Discussion
After identifying the cause for the formation of these impuri-
ties, we set out our goals to synthesize these molecules. Syn-
thesis of impurity A 2 was achieved by using a twostep
straight forward strategy (Scheme 3). Initially isopropyl
trifluoroacetate 10 was reacted with 30-methylacetophenone
11 in toluene with sodium methoxide as a base to afford
Scheme 1. Commercial process for the synthesis of celecoxib (1).
Scheme 2. Pathways for the formation of impurities A (2) and B (3).
¶These authors equally contributed in this work.
Scheme 3. Synthetic route of impurity A.
Bull. Korean Chem. Soc. 2019
© 2019 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Wiley Online Library
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Communication
ISSN (Print) 0253-2964 | (Online) 1229-5949
BULLETIN OF THE
KOREAN CHEMICAL SOCIETY
HPLC Analysis of the Compounds. The HPLC analysis
of crude celecoxib drug in our method showed the targeted
impurities were present in trace amounts which were taken
up for further HPLC analysis. In the initial analysis, crude
celecoxib drug has the assay of 99.12% at retention time of
20.21 min, whereas the impurity A and impurity B were
observed at retention times 18.80 and 21.66 min, respec-
tively (Figure 1). HPLC analysis of the impurities synthe-
sized were matched with the impurities in the drug, the
synthesized molecules were highly pure with assay of
98.63% and 98.30% for impurity A and impurity B,
respectively.
In summary, the origins for the formation of these impu-
rities A & B during process development were hypothe-
sized, synthesized and characterized in this report; which
were obtained with the overall yield of 80% and 23%,
respectively. A robust HPLC method also has been devel-
oped to calculate the assay of these impurities as 98.6%
and 98.3%.
Scheme 4. Synthetic route of impurity B.
4,4,4-trifluoro-1-(m-tolyl)butane-1,3-dione, 8 with a good
yield (87%). Further, 8 was added to 4-hydrazinobenzenesul-
fonamide hydrochloride 7 in ethyl acetate, the impurity A
2 was obtained as white solid (5.15 g) with an excellent yield
of 92.0%.
Impurity B was synthesized in a single step by using
mild condition (Scheme 4). To a solution of (E)-4,-
4,4-trifluoro-1-(p-tolyl)but-2-en-1-one 12 and 4-hydrazino-
benzenesulfonamide hydrochloride 7 in DMF sodium
methoxide in methanol was added. After the addition, reac-
tion mixture was heated to 100 ꢀC till the starting materials are
consumed. The impurity B 3 was isolated and purified by col-
umn chromatography as an off-white solid (120 mg, 22.5%)
with high purity. 19F NMR confirms that the impurities were
regio-isomers of celecoxib (see supporting information).
Acknowledgment. This work was supported by the
National Research Foundation of Korea grants funded by
the Korea Government (MSIP) (MRC 2017R1A5A201
5541, and Basic Science Research Program 2017R1D
1A1B03) and the International Science and Business Belt
Program through the Ministry of Science, ICT and Future
Planning (2017K000490). This work was also supported by
Post-doctoral Fellowship program funded by the Ministry
of Education of the Republic of Korea through the
Chungbuk National University in 2018 (M. V).
Supporting Information. Experimental section along with
1H, 13C, 19F NMR, HRMS, and HPLC spectral data are
available at the online version of this communication.
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Figure 1. HPLC chromatogram for celecoxib (1), impurity A (2)
and impurity B (3).
Bull. Korean Chem. Soc. 2019
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